The brain pathology in Alzheimer’s disease involves both neurofibrillary tangles rich in the protein tau and plaques containing amyloid-β peptide (Aβ), but the relative contribution of each to cognitive impairment is unclear. Roberson et al. found that cognitive and neuronal deficits in two transgenic mouse models of Alzheimer’s disease are prevented when endogenous tau production is eliminated or reduced by 50%. The effect of tau reduction was robust, despite the absence of tau mutations, hyperphosphorylation, overexpression, or aggregation into neurofibrillary tangles in these models. Tau reduction did not block plaque-associated neuritic dystrophy, indicating that neuritic dystrophy can be dissociated both from tau and from Aβ-induced cognitive impairments.